Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report

Abstract

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

Keywords: CQAs; IVIVC; IVIVR; PBBM; bioequivalence; biopredictive dissolution; modeling; permeability; precipitation; solubility.

Figure 1

Simulated concentration versus time profiles (solid line) and observed profiles with %CV (open squares) for oral solution (left panel), initial simulation for the tablet (middle panel), and simulation for the tablet following refinement of the model (right panel).

Figure 2

Overview of Day 1 presentations and BO sessions.

Figure 3

Belinostat in vitro and in vivo performance. Left: Concentrations in an in vitro gastric-to-intestinal transfer dissolution test (solid lines) were calculated with measured amorphous solubilities in gastric media (dashed lines). Right: Plasma concentration–time profiles in fasted beagle dogs (50 mg dose, n = 4).

Figure 4

Itraconazole in vitro and in vivo performance. Left: Concentrations in the intestinal donor medium of an in vitro membrane flux test. Right: Plasma concentration–time profiles in fasted rats (50 mg/kg, n = 6).

Figure 5

Methods to integrate dissolution in a PBBM.

Figure 6

Comparative micelle sizes.

Figure 7

Comparative prediction of Z-factor and P-PSD fitted on medium without a surfactant to predict dissolution in media with a surfactant. Data generated on acalabrutinib batch L0505009 capsule dissolution.

Figure 8

Presented decision tree to choose a dissolution model for introduction into PBBM.

Figure 9

Presented decision tree on how to test for drug precipitation and apply it to a PBBM. An explanation for “high quality human PK data” can be found in the main text. SAD Single ascending dose study (dose escalation study).